Comparative Mammalian Genomics

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Canine Genetics The tremendous phenotypic diversity of modern dog breeds represents the end point of a 20,000-year experiment. Each breed has undergone strong artificial selection for morphologic and behavioral traits to create populations with unique traits. As a result, there is strong phenotypic homogeneity within breeds as well as disease predispositions. These traits are explored in depth in the Ostrander lab. Canine Whole Genome Sequence We have continued our work on Dog10K, where our lab plays a Co-Leadership role with Drs. Guo-Dong Wang and Yaping Zhang from the Chinese Academy of Sciences. Working with 18 other labs across the world we aim to generate whole genome sequence (WGS) for 10,000 canines in the next five years. Thus far, about 3000 are completed. Sequence from samples contributed by the Ostrander lab have been made public with the rest of the consortium data currently becoming available. The goal is to sequence (20-30x) multiple dogs from each of the 300 registered breeds from the U.S., Africa, Europe, and Asia as well as mixed breeds, village dogs, and wild canids (Ostrander et al., 2019; Wang et al., 2019). In a separate effort, we performed an depth examination of WGS sequence from 772 dogs (Plassais et al., 2019) documenting over 91 million single nucleotide and small indels, thus creating the largest catalog of genomic variation for a companion animal species to date. Using both selective sweep analyses and genome wide association studies (GWAS) we identified strong impact variants associated with 16 phenotypes, including body weight variation, which highlights genes that, when mutated in humans, contribute to fatty acid metabolism, obesity and metabolic syndrome. Other variants, such as those controlling ear size and shape, produce hearing disorders when mutated in humans. Others are associated with aging. Still others are associated with fur type (Parker et al., 2019; Whitaker et al., 2020). We thus demonstrate that GWAS scans performed with WGS are powerful methods for finding not only genes but also variants underlying complex traits, thus expanding the utility of companion animal systems for the study of mammalian biology (Plassais et al., 2019; Whitaker et al., 2019). Aging We have initiated studies on aging and lifespan in dogs. We first characterized the methylomes of 104 Labrador retrievers spanning a 16-year age range, achieving >150 coverage within mammalian syntenic blocks (Wang et al., 2020). Comparison with human methylomes reveals a nonlinear relationship that translates dog-to-human years and aligns the timing of major physiological milestones between the two species, with extension to mice. Conserved changes center on developmental gene networks which are sufficient to translate age and the effects of anti-aging interventions across multiple mammals. These results establish methylation not only as a diagnostic age readout, but also as a cross-species translator of physiological aging milestones. Additional studies on larger datasets are underway. Canine Population Structure and Mendelian Disease Gene Mapping We have continued our large and continuous study of canine breed structure (Parker et al., 2017) in order to better inform disease mapping studies. We assembled the most diverse dataset of dog breeds in existence, reflecting extensive phenotypic variation and heritage. We continue to uncover geographic patterns of development and the independent origins of common traits. Our analyses characterizes the complexities of breed development (Ali et al., 2020), resolving longstanding questions regarding breed origin, the effect of migration on geographically distinct breeds and, by inference, transfer of trait and disease alleles among dog breeds (Marchant et al., 2019). We have shown we can track the history of variant alleles, offering predictions as to additional breeds where specific diseases may appear next. This work is foundational to all studies in dog genetic disease mapping as it informs study design by determining how breeds should be partitioned for each analyses. Breed Origins We recently completed a whole genome comparison of two types of dog breeds: those that are highly athletic and include the sport-hunting breeds, and terriers, which are known for their hyperactivity (Kim et al., 2018). These are groups at the ends of a continuum in both form and function. We found that genes underlying cardiovascular, muscular, and neuronal function are under strong selection in sport-hunting breeds. We also found associations with genes for hyperactivity, autism and attention disorders in terriers. The latter result is one that we are currently expanding as we seek to identify variants responsible for stereotypical behaviors in subsets of terriers and determine their role in humans. A natural outgrowth of this work has been our continued collaborations to better understand the process of domestication. Such studies highlight loci that are particularly malleable, providing insights into the genes that are likely most important in understanding human variation. We are now co-leading a study with Greger Larson to examine genome sequence from bones from hundreds of ancient dogs from the Americas with an aim of understanding both the migration of dogs and people during early settlement. Canine Cancer We remain firmly committed to mapping canine cancer genes for histiocytic sarcoma, invasive bladder cancer and gastric cancer. We examined RNAseq expression patterns of canine invasive urothelial carcinomas and found two distinct tumor clusters and shared regions of dysregulation with human bladder tumors (Parker et al., 2019). Because invasive urothelial carcinoma (iUC) is highly similar between dogs and humans in terms of pathology, response to treatment and age at onset, the dog is an excellent model for testing and development of targeted drugs benefiting both canines and humans. We performed RNAseq on canine tumor and normal tissues identifying a set of enrichment profiles that distinguishing iUC tumors with and without BRAFV595E (BRAFV600E in humans) mutations, as well as genomic regions harboring excessive numbers of dysregulated genes. BRAFV595E carrying tumors shared significantly more dysregulated genes than BRAF wild-type tumors, and vice versa, with 398 genes differentiating the two clusters. Key genes are those for cell cycle regulation, immune response, and membrane transport. We have summarized and the strengths of the dog model for studies of human cancer in a recent review (Ostrander et al., 2019). We continue to partner with collaborators on studies of transmissible tumors. Building on our earlier collaboration (Magres et al., 2018), we show that a single point mutation in the 5' untranslated region of the putative tumor suppressor RASL11A significantly contributes to tumor regression (Magres et al.,2019). RASL11A was expressed in regressed tumors but silenced in wild-type, nonregressed tumors, consistent with its downregulation in human cancers. By extension, the work shows that RASL11 activation may provide a general mechanism for tumor inhibition. Rare and Endangered Dogs The Ostrander lab remains committed to helping the larger animal genomics community answer questions in the field of conservation biology. We received a remarkable opportunity to perform nuclear genome studies on samples collected from a rare siting of three highland wild dogs from Papua, Indonesia. We hypothesized that these were actually New Guinea Singing dogs, a species thought to have gone extinct in the wild and existing only in conservation centers. Performing the first nuclear genome analysis of highland wild dogs we show that they are, indeed, representatives of the New Guinea Singing dog, and are thus candidates to rescue this unusual, near extinct species (Surbatki et al., 2020).